2-Phenylacetylenesulfonamide (PAS) induces p53-independent apoptotic killing of B-chronic lymphocytic leukemia (CLL) cells.
2-Phenylacetylenesulfonamide (PAS) induces p53-independent apoptotic killing of B-chronic lymphocytic leukemia (CLL) cells.
We studied the actions of 2-phenylacetylenesulfonamide (PAS) on B-chronic lymphocytic leukemia (CLL) cells. PAS (5-20 microM) initiated apoptosis within 24 hours, with maximal death at 48 hours asassessed by morphology, cleavage of poly(ADP-ribose) polymerase (PARP), caspase 3 activation, and annexin V staining. PAS treatment induced Bax proapoptotic conformational change, Bax movement from the cytosol to the mitochondria, and cytochrome c release, indicating that PAS induced apoptosis via the mitochondrial pathway. PAS induced approximately 3-fold up-regulation of proapoptotic Noxa protein and mRNA levels. In addition, Noxa was found unexpectedly to be bound to Bcl-2 in PAS-treated cells. PAS treatment of CLL cells failed to up-regulate p53, suggesting that PAS induced apoptosis independently of p53. Furthermore, PAS induced apoptosis in CLL isolates with p53 gene deletion in more than 97% of cells. Normal B lymphocytes were as sensitive to PAS-induced Noxa up-regulation and apoptosis as were CLL cells. However, both T lymphocytes and bone marrow hematopoietic progenitor cells were relatively resistant to PAS. Our data suggest that PAS may represent a novel class of drug that induces apoptosis in CLL cells independently of p53 status by a mechanism involving Noxa up-regulation.
1217-1225
Steele, Andrew J.
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Prentice, Archibald G.
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Hoffbrand, A. Victor
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Yogashangary, Birunthini C.
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Hart, Stephen M.
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Lowdell, Mark W.
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Samuel, Edward R.
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North, Janet M.
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Nacheva, Elisabeth P.
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Chanalaris, Anastasios
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Kottaridis, Panagiotis
22c56556-14cf-4a55-aaa9-e8ac493d463b
Cwynarski, Kate
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Wickremasinghe, R. Gitendra
6a90cc2b-8db5-45c2-ab57-7a1341b88bb2
6 August 2009
Steele, Andrew J.
4349f6aa-2e3a-49a8-be73-7716056ae089
Prentice, Archibald G.
a834a471-b816-4c3a-a3d4-70fa8dd2c982
Hoffbrand, A. Victor
f33e01e3-5c17-40fd-b66d-155e4f3bbffe
Yogashangary, Birunthini C.
309cbe4c-8d44-43e7-b744-453c4acd3d29
Hart, Stephen M.
43396380-899f-44e0-86c3-3aa10aae993c
Lowdell, Mark W.
399d3d5b-dcd3-4b23-a6f9-7141c0717f56
Samuel, Edward R.
33ab7fcf-e1fe-455b-8a7e-24f641ef903b
North, Janet M.
0552cf6f-6c30-4852-8e7b-c9c3cb53dfe5
Nacheva, Elisabeth P.
3052e0f3-bd51-463e-a4e0-5e69513e6ab2
Chanalaris, Anastasios
72d46901-69ac-4892-b713-4963b1b5d14f
Kottaridis, Panagiotis
22c56556-14cf-4a55-aaa9-e8ac493d463b
Cwynarski, Kate
34d6aef4-8106-40ee-9609-b44460ccb971
Wickremasinghe, R. Gitendra
6a90cc2b-8db5-45c2-ab57-7a1341b88bb2
Steele, Andrew J., Prentice, Archibald G., Hoffbrand, A. Victor, Yogashangary, Birunthini C., Hart, Stephen M., Lowdell, Mark W., Samuel, Edward R., North, Janet M., Nacheva, Elisabeth P., Chanalaris, Anastasios, Kottaridis, Panagiotis, Cwynarski, Kate and Wickremasinghe, R. Gitendra
(2009)
2-Phenylacetylenesulfonamide (PAS) induces p53-independent apoptotic killing of B-chronic lymphocytic leukemia (CLL) cells.
Blood, 114 (6), .
(doi:10.1182/blood-2008-11-190587).
(PMID:19515722)
Abstract
We studied the actions of 2-phenylacetylenesulfonamide (PAS) on B-chronic lymphocytic leukemia (CLL) cells. PAS (5-20 microM) initiated apoptosis within 24 hours, with maximal death at 48 hours asassessed by morphology, cleavage of poly(ADP-ribose) polymerase (PARP), caspase 3 activation, and annexin V staining. PAS treatment induced Bax proapoptotic conformational change, Bax movement from the cytosol to the mitochondria, and cytochrome c release, indicating that PAS induced apoptosis via the mitochondrial pathway. PAS induced approximately 3-fold up-regulation of proapoptotic Noxa protein and mRNA levels. In addition, Noxa was found unexpectedly to be bound to Bcl-2 in PAS-treated cells. PAS treatment of CLL cells failed to up-regulate p53, suggesting that PAS induced apoptosis independently of p53. Furthermore, PAS induced apoptosis in CLL isolates with p53 gene deletion in more than 97% of cells. Normal B lymphocytes were as sensitive to PAS-induced Noxa up-regulation and apoptosis as were CLL cells. However, both T lymphocytes and bone marrow hematopoietic progenitor cells were relatively resistant to PAS. Our data suggest that PAS may represent a novel class of drug that induces apoptosis in CLL cells independently of p53 status by a mechanism involving Noxa up-regulation.
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Published date: 6 August 2009
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Local EPrints ID: 178121
URI: http://eprints.soton.ac.uk/id/eprint/178121
ISSN: 0006-4971
PURE UUID: a9f3de8c-2e4f-46ab-a3ca-299fd42549ad
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Date deposited: 23 Mar 2011 10:07
Last modified: 14 Mar 2024 02:57
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Author:
Archibald G. Prentice
Author:
A. Victor Hoffbrand
Author:
Birunthini C. Yogashangary
Author:
Stephen M. Hart
Author:
Mark W. Lowdell
Author:
Edward R. Samuel
Author:
Janet M. North
Author:
Elisabeth P. Nacheva
Author:
Anastasios Chanalaris
Author:
Panagiotis Kottaridis
Author:
Kate Cwynarski
Author:
R. Gitendra Wickremasinghe
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